Abused drugs produce long-lasting changes in behaviors via biochemical mechanisms that are largely unknown. Drug-altered changes in expression of specific genes in the brain can provide a major window on possible biochemical substrates for ddiction. To further explore this area, we are now increasingly focused on array hybridization techniques that has allow identification of dozens of distinct cDNAs that correspond to candidate drug- regulated genes expressed in brain. During this year, we have enhanced characterization of candidate genes whose expression is regulated by amphetamine, cocaine and morphine. We have identified a human haplotype in the morphine-regulated gene, NrCAM, that is associated with human substance abuse vulnerability in human genome scanning studies from this laboratory. During this year, we have reported the KEPI gene. We have also identified a relative of this initial morphine-upregulated gene, KEPI, that we have termed "GBPI" as a second protein-kinase-C dependent phosphoprotein whose phosphorylation causes it to become a powerful inhibitor of protein phosphatase 1 activity and is expressed in gut and in brain. Using microarrays, we have been able to detect reproducible positive hybridization signals from ca 38% of the genes sampled oligonucleotide DNA microarrays, and to identify the ca 1-2% that are reproducibly regulated more than 2-fold by knockouts or drugs. We have characterized amphetamine-induced changes as upregualating a number of genes acutely and downregulating them chronically, in work accepted for publication in this year. These data provide powerful substrates for further convergence with studies of human drug abuse vulnerability genome scans and with studies of mechanisms of addiction neurobiology.